EP2689249A1 - Assay for screening compounds that selectively decrease the number of cancer stem cells - Google Patents
Assay for screening compounds that selectively decrease the number of cancer stem cellsInfo
- Publication number
- EP2689249A1 EP2689249A1 EP12760950.1A EP12760950A EP2689249A1 EP 2689249 A1 EP2689249 A1 EP 2689249A1 EP 12760950 A EP12760950 A EP 12760950A EP 2689249 A1 EP2689249 A1 EP 2689249A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- cells
- cscs
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- population
- decreases
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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Definitions
- determining whether the candidate agent reduces the survival or growth or increases differentiation of the CSC relative to a CSC that has not been contacted with the candidate agent by:
- a further embodiment of the present invention is an agent for selectively killing CSCs identified by any methods of the present invention.
- Figure 2b shows the heat map of developmental genes, organized by hierarchical clustering using Cluster and Treeview. Color coding in red indicates high levels of expression and coding in green indicates low levels of expression. The signal values have been log2 transformed.
- Figure 2c shows immunoblotting and protein quantification of cell lysates of matched parental and Docetaxel resistant cells for epithelial differentiation markers, prostate related markers, MHC class I antigens, WNT/ ⁇ -catenin pathway proteins, NOTCH signaling protein and Hedgehog signaling pathway proteins.
- Figure 5 shows that chemotherapy enriches for cancer stem cells with a CK19-negative, GFP negative phenotype.
- Figure 5a shows a schematic representation of the working hypothesis.
- Figure 5b shows representative serial imaging of stably transfected cells treated with Docetaxel (10 riM) at various time points as indicated. Unsorted DU145-CK19 promoter-GFP stable cells were treated with Docetaxel (10nM) for 48h and filmed by time-lapse microscopy to study their behavior. Serial images of a representative experiment are included where a black arrow points to a GFP- cell that undergoes cell division and survives under chemotherapy, while GFP expressing cells start dying after mitotic arrest.
- Figure 13 shows Docetaxel resistance reversibility linked to a recovery in the differentiated cell phenotype in DU145 and 22RV1 cells.
- the left panel of Figure 13 shows western blot analysis and the right panels of Figure 13 show histogram protein quantification of the expression of epithelial differentiation markers (CK18 and CK19) and HLA class I antigens in parental sensitive cells, Docetaxel acquired resistant cells and Docetaxel reversed resistant cells.
- Reversed resistant cells display higher protein expression levels than Docetaxel acquired resistant cells, achieving similar levels than those observed in parental sensitive cells.
- Figure 14b shows immunofluorescence staining for HLA class I (red) and GFP (green) of DU145 parental cells stably transfected with the pCK19-GFP plasmid.
- a white arrow in the merge panel points to a cell lacking the expression of HLA class I and GFP.
- Flow cytometry quantification confirms the co-expression of GFP and HLA-class I antigens.
- Cells that express GFP are HLA class l-positive, whereas cells that do not express GFP are also HLA class l-negative.
- Figure 16 shows quantification of GFP/HLA subpopulations in tumour xenografts generated from injection of GFP-negative/HLA-negative sorted cells.
- Representative flow cytometry analysis plot and quantification of GFP/HLA subpopulations of cells in tumour xenografts show that two distinct populations of cells are observed: a major population of GFP-positive/HLA-positive cells and a smaller population of cells with a GFP-negative/HLA-negative phenotype.
- HLA ⁇ means having no major histocompatibility complex (MHC) class I molecules.
- MHC major histocompatibility complex
- the MHC is a set of molecules displayed on cell surfaces that are responsible for lymphocyte recognition and antigen presentation.
- the MHC class I molecules present antigen to cytotoxic T-cells. MHC I molecules are found on almost all types of body cells.
- Identifying the HLA " cells from a cancer cell population may be accomplished using any conventional or known technique that identifies cells based on, e.g., expression, or non-expression, of particular cell surface markers and maintains the viability of the cell.
- the identification is carried out by a Fluorescence- activated cell sorting (FACS) analysis as disclosed in more detail in the Examples.
- FACS Fluorescence- activated cell sorting
- capability to self-renew means, e.g., that a CSC has the ability to go through numerous cycles of cell division while maintaining its undifferentiated state.
- the population of cells in accordance with the invention may also be a mammalian CSC line that is enriched for cells that are HLA ⁇ and HLA II " .
- Mammalian refers preferably to human, mouse, or other research mammal, such as e.g. , a rat.
- enriched means a cancer cell line that has increased numbers of CSCs relative to a control cell line that has not been treated, with e.g. , an agent used to treat cancer.
- the increased numbers of CSCs may be transient, e.g., some of the CSC may differentiate, or may be of a longer duration.
- such a cell line may or may not be pure, e.g., substantially free of HLA + cells.
- CSCs may have at least one of the following properties: CD24 “ , CD133 " , Notch + , Gli1 + , Gli2 + , GFAP “ , Neurofil “ , and cytokeratin “ . Moreover, combinations of any or all of the foregoing are also contemplated.
- the CSCs may further have at least one of the following properties: capability to self-renew, undergo asymmetrical cell division, have tumorigenic capacity, have metastatic potential, have multi-differentiation properties, sensitive to Notch and Hedgehog inhibitors, and have broad chemoresistance. Moreover, combinations of any or all of the foregoing are also contemplated.
- the CSCs may be refractory to standard chemotherapy.
- "refractory” means resistant.
- a sample of cancer/tumor cells may be derived from a sample of cancerous material of a subject that is resistant to chemotherapy, or the CSCs may be obtained from a cancer cell line that is resistant to chemotherapy. Methods for generating such resistant cancer cell lines are known in the art and disclosed in further detail in the Examples.
- a candidate agent is selected from the group consisting of a chemical, a biologic, and combinations thereof.
- a "biologic” means a substance which is derived from or produced by a living organism or synthesized to mimic an in wVo-derived agent or a derivative or product thereof.
- a biologic may be, for example, a nucleic acid, a polypeptide, or a polysaccharide.
- a "chemical” means a substance that has a definite chemical composition and characteristic properties and that is not a biologic.
- Non-limiting examples of chemicals include small organic compounds and small inorganic compounds.
- Non-limiting examples of candidate agents include Hedgehog and Notch inhibitors as disclosed in the Examples herein.
- a "cell viability" assay is an assay that identifies and/or separates live cells from dead cells.
- a non-limiting example of a cell viability assay is disclosed in the Examples.
- the determining step comprises carrying out a procedure selected from the group consisting of flow cytometry analysis, a cell viability assay, a cell differentiation assay, a cell division assay, and combinations thereof.
- determining whether the candidate agent reduces the survival or growth or increases the differentiation of the CSC relative to a CSC that has not been contacted with the candidate agent by:
- determining, using a cell viability assay, the percentage of viable cells in the treated and untreated population of cells iii. determining, using a cell differentiation assay, the percentage of non-CSC cells in the treated and untreated population of cells;
- a drug e.g., pharmaceutical formulation
- the modified nucleotide analog may be located for example at the 5'-end and/or the 3'-end of the nucleic acid molecule.
- Representative examples of nucleotide analogs may be selected from sugar- or backbone-modified ribonucleotides. It should be noted, however, that also nucleobase- modified ribonucleotides, i.e. ribonucleotides, containing a non-naturally occurring nucleobase instead of a naturally occurring nucleobase such as uridines or cytidines modified at the 5-position, e.g.
- Modified nucleotides and nucleic acids may also include locked nucleic acids (LNA), as disclosed in U.S. Patent Application Publication No. 20020115080. Additional modified nucleotides and nucleic acids are disclosed in U.S. Patent Application Publication No. 20050182005. Modifications of the ribose-phosphate backbone may be done for a variety of reasons, e.g., to increase the stability and half- life of such molecules in physiological environments, to enhance diffusion across cell membranes, or as probes on a biochip. Mixtures of naturally occurring nucleic acids and analogs may be made; alternatively, mixtures of different nucleic acid analogs, and mixtures of naturally occurring nucleic acids and analogs may be made.
- LNA locked nucleic acids
- organic compound refers to any carbon-based compound other than macromolecules such as nucleic acids and polypeptides.
- organic compounds may contain calcium, chlorine, fluorine, copper, hydrogen, iron, potassium, nitrogen, oxygen, sulfur and other elements.
- An organic compound may be in an aromatic or aliphatic form.
- Docetaxel is an anti-mitotic agent currently used as standard therapy in patients with hormone refractory prostate cancer (Petrylak et a/., 2004; Tannock et al.,
- CALM1 (calmodulin)
- HSP70 Heat shock protein
- IFI35 interferon, gamma
- Table 5 summarizes the tumour initiating capacity measured by tumour incidence (tumours/injections) and tumour latencies in weeks (mean ⁇ SD), when 10, 100 and 1000 HLA class I sorted and unsorted cells from primary prostate cancer tissues were injected.
- mice for each sorted cell population and cell dilution were injected twice in the upper flanks (HLA-negative) and lower flanks (HLA-positive). Unsorted cells from each tumour specimen were also injected.
- Tumour latency Injections Tumour latency Injections
- the tumor initiating capacity of cells from fresh human tissue samples was not related to any of the analyzed clinico-pathological characteristics of the cancer patients, neither associated with the percentage of HLA-negative cells.
- Tumours with aggressive clinico-pathological characteristics e.g., high grade, high tumour stage
- tumours with a high number/percentage of HLA-negative cells e.g., 1.5%) did not possess a significantly higher tumour initiating capacity.
- no association was observed between the percentage of HLA-negative cells and either tumour stage or tumour grade.
- Cyclopamine a plant derived hedgehog pathway antagonist that acts at the level of Smo (Taipale et al., 2000; Karhadkar et al., 2004; Chen et al., 2002), was utilized.
- Compound E is a highly active gamma-secretase inhibitor that blocks the proteolytic processing of Notch receptors (Seiffert et al., 2000).
- mice treated with the triple combination showed a significant (p ⁇ 0.05) delay in tumor first palpability of 5.1 weeks in DU145 and 3.8 weeks in 22RV1 xenografts, whereas this tumor delay was not significant in mice treated with Hedgehog or Notch inhibitors alone. (Figure 10c).
- Tumor xenografts in mice treated with the triple combination of drugs were first palpable after 18.3 ⁇ 3.1 , 13.8 ⁇ 2.5 and 20.1 ⁇ 3.3 weeks, compared to 13.8 ⁇ 2.5, 10.3 ⁇ 1.5 and 16.6 ⁇ 2.5 weeks in their corresponding controls. [0140] Taken together, these results show that the inhibition of these developmental pathways targets the cancer stem cell population delaying tumor initiation.
- HLA-negative phenotype is also shared by embryonic stem cells. It has been reported that human pre-implantation embryos are HLA class I and class II negative (Desoye et a/., 1988). This phenomenon precludes rejection based on expression of paternal antigens, until a blood-tissue barrier develops, in this situation being the placenta. In the context of cancer stem cells, such a histocompatibility negative phenotype has major clinical implications, since it explains host mutation permissiveness, as well as tumor spread and metastatogenic capabilities, since cancer stem cells would escape immune-surveillance.
- DU-145 and 22RV1 Human hormone-independent prostate cancer cell lines, DU-145 and 22RV1 , were obtained from American Type Culture Collection (ATCC) and maintained in RPMI 1640 medium (Gibco, Invitrogen Corp., Carlsbad, CA) supplemented with 10% FBS without antibiotics. Cells were grown at 37°C in a humidified atmosphere with 5% C0 2 . DU145 and 22RV1 cells were selected in order to generate a prostate cancer Docetaxel resistance model. This selection was based on the fact that both cell lines are hormone-refractory, a condition treated with Docetaxel in the clinical setting, and that they also exhibit distinct hormone-refractory phenotypes.
- Docetaxel resistant clones DU-145-DR and 22RV1-DR, were selected by culturing cells with Docetaxel in a dose-escalation manner. Initial culture was at 5 nM Docetaxel.
- RNA quality of all samples was tested by RNA electrophoresis and RNA LabChip analysis (Agilent Technologies, Inc., Santa Clara, CA) to ensure RNA integrity. Samples were prepared for analysis with Affymetrix Human U133 Plus 2.0 arrays according to the manufacturer's instructions.
- Genes differentially expressed in the Docetaxel resistant cells compared to the parental sensitive cells generated a list of commonly deregulated transcripts. This list was assessed by the DAVID Bioinformatics Resources, a web-based statistical hypergeometric test applied for enrichment analysis of gene ontology (GO) categories, which are, biological process, molecular function, and cellular component. GO categories enriched on the highest hierarchical level ( ⁇ level 5) at statistical significance (p ⁇ 0.01) were taken into consideration.
- GO gene ontology
- Immunofluorescence analyses were conducted on prostate cancer cell lines and formalin fixed paraffin-embedded tissue sections from human cancers and tumor xenografts.
- Primary antibodies included a combination of cytokeratin 19 and 18 (Abeam), pan-HLA class I (Abeam), green fluorescence protein (Abeam) and the following transcription factors: active ⁇ -Catenin (Millipore), activated Notch2 (Abeam), Gli1 (Santa Cruz), GH2 (Abeam) and androgen receptor (DAKO, Fort Collins, CO).
- Secondary antibodies used were Alexa Fluor® 594 (Invitrogen) and Alexa Fluor® 488 (Invitrogen).
- CK19 gene promoter region was amplified from DU145 cells genomic DNA by PCR with specific primer sets (Fw 5'-AACGCATGCTTTGGGGGGATG-3' (SEQ ID NO: 1) and Rv 5'-TCCCCCTTTACTCGGCCCCCAC-3' (SEQ ID NO: 2)) as described previously (Tripathi et al., 2005.
- the PCR products were digested with Ase I and Hind III and cloned into pEGFPNI vector (Clontech, Mountain View, CA) previously digested with the same enzymes.
- the CMV promoter was removed from the original vector and the GFP expression was under control of the CK19 promoter. The final construct was confirmed by digestion and sequencing analysis.
- Time-lapse videomicroscopy was used to assess asymmetrical cell division and Docetaxel subpopulation sensitivity of DU145 cells stably transfected with the pCK19-GFP promoter.
- Cells growing in 6-well plates at low confluence were placed in the stage inside an incubator chamber at 37°C, 50% humidity and in an atmosphere of 5% C0 2 .
- Unattended time-lapse movies of randomly chosen GFP+ and GFP- DU145 cells were performed with a Nikon Eclipse T/ inverted microscope.
- NIS Elements AR Nakon Inc., Melville, NY
- Imaging was performed using a 10x objective and images were captured using 200-ms exposure times for GFP and 20-ms for bright field every 30 minutes.
- mice For xenograft tumors, primary fluorescent conjugated antibodies to mouse CD45 (eBiosciences), mouse CD31 (Biolegend, San Diego, CA) and human HLA-class I (Abeam) were used to select live human cancer cells. Cells were suspended in 10 pg/ml DAPI to label dead cells and sorted on FACSAria Cell Sorting System (BD Biosciences). Different dilutions (10, 100 and 1 ,000 injected cells) of human prostate cancer HLA sorted cells (HLA class l-negative and HLA class I- positive) and unsorted cells, and 100 HLA sorted cells from other human cancer samples (primary injections) and derived xenografts (secondary injections) were injected into NOD/SCI D mice.
- mice for treatment arm e.g., Cyclopamine
- human prostate tumours 8 mice were included for each treatment arm. Mice were monitored every day until tumors formed. Animals were sacrificed if they showed any evidence of distress or if they lost more than 20% of their original body weight. Generated tumors were harvested and histologically confirmed.
- CKs cytokeratins
- Docetaxel resistant cells showed a significant decrease in both gene transcription and protein expression of low molecular weight CKs.
- DU145-DR cells showed a 6.25 and 16.6 fold decrease in the protein expression of CKs 19 and 18 respectively.
- 22RV1-DR showed a 14.3 and 6.7 fold decrease in such CKs when quantified and compared to the sensitive parental cells.
- Immunofluorescence staining of CK19 and CK18 confirmed their decreased expression in the Docetaxel resistant cells (Figure 2).
- high molecular weight CKs continued to be undetectable in the Docetaxel resistant cells as in their corresponding parental cells (data not shown), indicating that in the process of acquiring Docetaxel resistance, cells lose epithelial differentiation markers and do not undergo a shift from a luminal (low molecular weight CK) to a basal-like (high molecular weight CK) phenotype.
- 22RV1 cells which express prostate-related differentiation markers including AR, PSMA and PSA, showed a dramatic decrease of gene and protein expression levels of such markers when exposed to Docetaxel (Figure 2). 22RV1-DR cells showed a 16.6, 20.0 and 11.1 fold decrease in the protein expression of AR, PSMA and PSA respectively.
- NK Natural killer (NK) ligands gene expression that were deregulated in Docetaxel resistant cells (DU145-DR and 22RV1-DR) when compared to their parental sensitive cells (DU145 and 22RV1) are summarized in Table 9.
- NK natural killer
- Poliovirus receptor -4.1 Poliovirus receptor -4.1; -2.1 ⁇ 0.0001; ⁇ 0.05 poliovirus receptor-related 2 (herpesvirus -2.5;-1.7 ⁇ 0.05;NS
- DU145 parental cells were stably transfected with a plasmid containing the promoter of CK19 driving the expression of the green fluorescence protein (GFP) ( Figure 14a).
- GFP green fluorescence protein
- Figure 14a Co-expression of CK19 and GFP in DU145-CK19 promoter-GFP stable cells was confirmed by immunofluorescence ( Figure 14a).
- Flow cytometry quantification showed two distinct populations of cells, being the majority of cells positive for both GFP and CK19 (94.3 ⁇ 3.8%) and a discrete population of cells negative for both markers (5.6 ⁇ 4.1%). Few scattered cells outside these two main populations were observed which could represent transiting cells from one compartment to the other.
- stable insertion of the promoter construct in CK19/GFP negative cells was confirmed by PCR ( Figure 4c).
- HLA-class I expression can be used as a cell surface marker that identifies cells with the cancer stem cell functional property of tumour initiation
- parental cell lines DU145 and 22RV1 were sorted for HLA-class I and their tumour initiating capacity tested in NOD/SCID mice ( Figure 15). Similar to the results obtained with the DU145-CK19 promoter-GFP stable GFP-negative cells, only the HLA class l-negative cells exhibited tumour initiating capacity after dilution assays.
- HLA class l-negative cells displayed a statistically significant higher clonability than HLA class l-positive cells. Specifically, HLA class l-negative sorted cells from DU145 generated colonies in 31.6 ⁇ 7.5%, 17.1 ⁇ 3.6% and 22.0 ⁇ 4.9% when 10, 100 and 1000 cells were plated, respectively. In contrast, HLA class l-positive cells generated colonies in 5.0+8.3%, 8.0 ⁇ 3.3% and 5.5 ⁇ 1.5% when 10, 100 and 1000 cells were plated ( Figure 8). Similar results were observed with 22RV1 HLA class I sorted parental cells (data not shown).
- CK-negative/HLA-negative cells displayed nuclear expression of de-phosphorylated ⁇ -catenin in 63.9 ⁇ 22.6% of cells, cleaved Notch2 in 72.8 ⁇ 15.1 %, GN1 in 67.5 ⁇ 17.3%, and GH2 in 67 ⁇ 17.3%, whereas CK-positive/HLA-positive cells expressed nuclear de-phosphorylated ⁇ -catenin in only 5.8 ⁇ 11.9% of cells, cleaved Notch2 in 6.7 ⁇ 7.9%, Gli1 in 1.2 ⁇ 7.9%, and GH2 in 1.5 ⁇ 10.6% (Figure 7c).
- an in vitro high throughput assay was designed to screen compounds targeting this CSC population, and to determine whether CSCs are either selectively killed or differentiated. Implementation of this assay permits testing of a wide variety of drugs and facilitates the identification of compounds with a putative CSC inhibitory effect.
- Outcome 3 may be interpreted that neoplastic cells, but not the CSC population, has been targeted by the candidate agent, e.g., drug.
- Outcome 4 may be interpreted that no effect is produced by the candidate agent, e.g., drug, in either CSC or neoplastic differentiated cells.
- Candidate agents e.g., drugs that produce CSC depletion (outcome 1) or CSC differentiation (outcome 2) would be considered for further experimentation and characterization by means of standard in vitro and in vivo assays. Briefly, these assays aimed at confirming and validating early screening results, include: a) in vitro - apoptotic methods (e.g., annexin V), colony formation, and differentiation studies based on their correponding phenotypes (e.g., flow cytometry and immunohistochemical analyses); and b) in vivo - dilutional tumor initiation assays in immunocompromised mice.
- in vitro - apoptotic methods e.g., annexin V
- colony formation e.g., colony formation
- differentiation studies based on their correponding phenotypes
- correponding phenotypes e.g., flow cytometry and immunohistochemical analyses
- Embryonic stem cell microRNAs defining factors in induced pluripotent (iPS) and cancer (CSC) stem cells? Curr. Stem Cell Res. Ther. 4(3): 168-177 (2009).
- Ricci-Vitiani L. et al., Identification and expansion of human colon-cancer- initiating cells. Nature 445, 111-115 (2007). Ricci-Vitiani, L. et al., Colon cancer stem cells. J. Mol. Med. 87(11 ): 1097-1104 (2009).
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AU2012230850A1 (en) | 2013-04-18 |
DK2689249T3 (en) | 2016-08-29 |
PT2689249T (en) | 2016-09-20 |
KR20140016348A (en) | 2014-02-07 |
PL2689249T3 (en) | 2017-09-29 |
HK1191693A1 (en) | 2014-08-01 |
EP2689249A4 (en) | 2014-12-31 |
CN103688175A (en) | 2014-03-26 |
AU2012230850B2 (en) | 2015-08-27 |
WO2012129393A1 (en) | 2012-09-27 |
EP2689249B1 (en) | 2016-05-25 |
US20160187320A1 (en) | 2016-06-30 |
JP6002748B2 (en) | 2016-10-05 |
MX2013010997A (en) | 2014-06-23 |
BR112013024476B1 (en) | 2022-06-14 |
HUE030159T2 (en) | 2017-05-29 |
IL228171A (en) | 2017-09-28 |
MX345893B (en) | 2017-02-22 |
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